Differences in degree of trapping of low-affinity uncompetitive N-methyl-D-aspartic acid receptor antagonists with similar kinetics of block

This study characterizes the trapping of block of N-methyl-D-aspartic acid (NMDA)-induced currents by three structurally distinct, use-dependent NMDA receptor antagonists with similar rapid on-off rates. The antagonism of who le-cell currents in cultured rat cortical neurons by AR-R15896AR, ketamine, and memantine was examined. All three compounds produced a steady-state bl ock after a 30-s coapplication, which was fully relieved after 50 s of NMDA exposure. The amplitudes of block caused by 50 mu M AR-R15896AR, 10 mu M k etamine, or 10 mu M memantine were not significantly different, being 82 +/ - 1%, 80 +/- 2%, and 81 +/- 2%, respectively. All three NMDA receptor antag onists exhibited trapping of block that was not significantly increased by extending the agonist/antagonist coapplication beyond 30 s. Although the in itial blocks were similar, after 120 s of washout without agonist present, there were significant differences in trapping of block between antagonists , as only 54 +/- 3% of the AR-R15896AR block, 86 +/- 1% of the ketamine blo ck, and 71 +/- 4% of the memantine block remained trapped. The lack of comp lete trapping is consistent with closed-channel egress by these compounds. Higher antagonist concentrations produced larger initial blocks, but the de gree of trapping block was not significantly different from that at lower a ntagonist concentrations. The results demonstrate that differences in the d egree of trapping exist among use-dependent NMDA receptor antagonists even when on and off rates are similar. These differences are correlated with me asures of therapeutic index.